Investigating the intrinsic link between hepatitis C virus entry and sensitivity to neutralising antibodies.

Hepatitis C virus (HCV) establishes a chronic infection in ~80% of cases, this feature is largely attributable to the array of immune countermeasures exhibited by the virus, including various neutralising antibody (nAb) evasion mechanisms. Current evidence suggests that nAb evasion incurs a fitness cost to the virus by making virus entry less efficient. As such, HCV is likely to perform a balancing between opposing selection pressures: the necessity to evade nAbs vs the benefits of efficient entry. We are investigating the molecular mechanisms that underlie this evolutionary antagonism. The project is comprised of three phases:

1) Quantifying the relationship between virus entry and nAb sensitivity.
We have identified a pair of closely related HCV variants one of which is highly resistant to nAbs, whereas the other is highly sensitive. We hypothesize that these differences in nAb sensitivity will be accompanied by changes in entry efficiency. We will investigate this using an array of virus entry assays combined with mathematical modeling analysis by a collaborator. This will allow us to measure the fitness cost associated with nAb evasion.

2) Investigate the link between nAb evasion and virus entry using clinically relevant patient derived viruses.
Having established the tools to evaluate virus entry efficiency we will focus our investigation on a range of diverse patient derived viruses. In particular, we are interested in the founder strains of HCV that transmit between individuals. These are responsible for the propagation of the HCV pandemic and are the most relevant strains for vaccine development. We will study whether these viruses have particular hallmarks, in virus entry or nAb evasion. For instance, do founder viruses favor efficient entry over nAb evasion?

3) Can perturbing the efficiency of virus entry augment the natural nAb response?Hepatitis C virus (HCV) establishes a chronic infection in ~80% of cases, this feature is largely attributable to the array of immune countermeasures exhibited by the virus, including various neutralising antibody (nAb) evasion mechanisms. Current evidence suggests that nAb evasion incurs a fitness cost to the virus by making virus entry less efficient. As such, HCV is likely to perform a balancing between opposing selection pressures: the necessity to evade nAbs vs the benefits of efficient entry. We are investigating the molecular mechanisms that underlie this evolutionary antagonism. The project is comprised of three phases: